Compositions and methods for non-surgical treatment of ptosis

ABSTRACT

Provided are pharmaceutical compositions, and methods of use of the compositions, for the non-surgical treatment of ptosis (eyelid droop). In one embodiment the composition includes oxymetazoline 0.1% formulated for topical administration to an eye. In one embodiment the composition includes a synergistic combination of oxymetazoline and phenylephrine, formulated for topical administration to an eye. Oxymetazoline alone causes no pupillary dilation (mydriasis), and a synergistic combination of oxymetazoline and phenylephrine induces no clinically significant mydriasis. In addition, to providing desirable cosmetic effects, the compositions and methods of the invention can improve visual fields otherwise compromised by ptosis.

RELATED APPLICATIONS

This application is a Continuation of application Ser. No. 16/577,262filed Sep. 20, 2019, which is a continuation of U.S. patent applicationSer. No. 15/837,325 filed on Dec. 11, 2017, which is a continuation ofU.S. patent application Ser. No. 14/625,099, filed Feb. 18, 2015, nowU.S. Pat. No. 9,867,808, which is a continuation of U.S. patentapplication Ser. No. 13/218,584, filed Aug. 26, 2011, now abandoned,which claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional PatentApplication No. 61/448,949, filed Mar. 3, 2011.

BACKGROUND OF THE INVENTION

Ptosis is abnormal partial or complete drooping of the upper eyelid.Ptosis occurs when the muscles that raise the eyelid (levator palpebraesuperioris and Müller's muscles) are not strong enough to do soproperly. It can affect one eye or both eyes and is more common in theelderly, as muscles in the eyelids may begin to deteriorate. Fatigue isa common reversible cause of ptosis, giving an affected individual anappearance characterized by “tired eyes.”

It is common for affected individuals to seek medical help to treatptosis, as it creates a tired-looking appearance, thereby interferingwith social relationships. In more severe cases ptosis can eveninterfere with vision as the upper lid partially or totally covers thepupil. While there are numerous recognized causes of ptosis, it iscommon to treat ptosis with ophthalmic plastic surgery. Non-surgicalmodalities for the treatment of ptosis include the use of “crutch”glasses or special scleral contact lenses to support the eyelid.

SUMMARY OF THE INVENTION

The invention provides compositions and methods useful in the treatmentof ptosis. Compositions of the invention include an effective amount ofa long-acting alpha adrenergic agonist and, optionally, a short-actingalpha adrenergic agonist. In one embodiment the compositions areformulated for topical administration to the eye. As described herein,the compositions and methods of the invention can be used to treatptosis in a non-surgical method. The methods provide long-lastingreversible treatment for ptosis in suitable subjects.

It has been discovered, in making the instant invention, thatoxymetazoline unexpectedly can be administered to an eye to treat ptosiswithout affecting pupil size. This observation was unexpected becauseoxymetazoline is an alpha adrenergic agonist, and other alpha adrenergicagonists are known commonly to cause pupillary dilation (mydriasis).

More particularly, it has been discovered that oxymetazoline, at leastin the amounts and at the concentrations used in accordance with theinstant invention, does not cause mydriasis. Accordingly, in certainembodiments the compositions and methods of the invention are disclosedto be useful to treat ptosis without causing mydriasis commonly obtainedwith alpha adrenergic agonists topically administered to the eye.

It has also been discovered, in making the instant invention, thatoxymetazoline and phenylephrine unexpectedly can be used in combinationto treat ptosis, with a synergistic effect. More particularly, it hasbeen discovered that the effect on lid aperture of a combination ofoxymetazoline and phenylephrine is greater than the sum of the effectsof oxymetazoline alone and phenylephrine alone. Moreover, suchcombination can also be used to treat ptosis without causing clinicallysignificant mydriasis.

The compositions and methods of the invention are disclosed to be usefulto treat visual field defects arising from ptosis.

An aspect of the invention is a method for treating ptosis in a subject.The method includes the step of administering an effective amount ofoxymetazoline to the exterior surface of an eye of a subject in need ofsuch treatment.

In one embodiment the administering results in at least a 1 millimeter(mm) increase in the vertical separation of the upper and lower lids ofthe eye. In one embodiment the administering results in at least a 10percent increase in the vertical separation of the upper and lower lidsof the eye.

In one embodiment the oxymetazoline is formulated as a pharmaceuticalcomposition comprising at least 0.05 weight percent oxymetazoline in anophthalmologically acceptable carrier. In one embodiment theoxymetazoline is provided as a pharmaceutically acceptable salt ofoxymetazoline.

In one embodiment the administering is administering as a single drop.

In one embodiment the administering is administering at least oncedaily. In one embodiment the administering is administering once daily.

In one embodiment the subject does not have an allergic ocular conditioncalling for treatment of the eye with oxymetazoline. In one embodimentthe subject does not have eyelid swelling. In one embodiment the subjecthas not undergone refractive eye surgery.

An aspect of the invention is a method for treating ptosis in a subject.The method includes the step of administering an effective amount of along-acting alpha adrenergic agonist and an effective amount of ashort-acting alpha adrenergic agonist to the exterior surface of an eyeof a subject in need of such treatment.

In one embodiment the long-acting alpha adrenergic agonist isoxymetazoline or a pharmaceutically acceptable salt thereof.

In one embodiment the short-acting alpha adrenergic agonist isphenylephrine or a pharmaceutically acceptable salt thereof.

In one embodiment the administering results in at least a 1 millimeter(mm) increase in the vertical separation of the upper and lower lids ofthe eye. In one embodiment the administering results in at least a 10percent increase in the vertical separation of the upper and lower lidsof the eye.

In one embodiment the oxymetazoline is formulated as a pharmaceuticalcomposition comprising at least 0.05 weight percent oxymetazoline in anophthalmologically acceptable carrier.

In one embodiment the long-acting alpha adrenergic agonist is providedas a pharmaceutical composition comprising at least 0.1 weight percentoxymetazoline and the short-acting alpha adrenergic agonist is providedas a pharmaceutical composition comprising at least 0.15 weight percentphenylephrine. In one embodiment the long-acting alpha adrenergicagonist is provided as a pharmaceutical composition comprising at least0.1 weight percent oxymetazoline and the short-acting alpha adrenergicagonist is provided as a pharmaceutical composition comprising at least0.25 weight percent phenylephrine. In one embodiment the long-actingalpha adrenergic agonist is provided as a pharmaceutical compositioncomprising 0.1 weight percent oxymetazoline and the short-acting alphaadrenergic agonist is provided as a pharmaceutical compositioncomprising 0.25 weight percent phenylephrine.

In one embodiment the oxymetazoline is formulated together withphenylephrine as a pharmaceutical composition comprising at least 0.1weight percent oxymetazoline and at least 0.15 weight percentphenylephrine in an ophthalmologically acceptable carrier. In oneembodiment the oxymetazoline is formulated together with thephenylephrine as a pharmaceutical composition comprising at least 0.1weight percent oxymetazoline and at least 0.25 weight percentphenylephrine in an ophthalmologically acceptable carrier. In oneembodiment the oxymetazoline is formulated together with thephenylephrine as a pharmaceutical composition comprising 0.1 weightpercent oxymetazoline and 0.25 weight percent phenylephrine in anophthalmologically acceptable carrier.

In one embodiment the administering is administering as a single drop.

In one embodiment the administering is administering at least oncedaily. In one embodiment the administering is administering once daily.

In one embodiment the subject does not have an allergic ocular conditioncalling for treatment of the eye with oxymetazoline. In one embodimentthe subject does not have eyelid swelling. In one embodiment the subjecthas not undergone refractive eye surgery.

An aspect of the invention is a pharmaceutical composition, comprisingoxymetazoline, a short-acting alpha adrenergic agonist, and apharmaceutically acceptable carrier, formulated for topical ophthalmicuse.

In one embodiment the short-acting alpha adrenergic agonist isphenylephrine.

In one embodiment the oxymetazoline is present at a concentration of atleast 0.1 weight percent.

In one embodiment the phenylephrine is present at a concentration of0.15 to 1.5 weight percent.

In one embodiment the oxymetazoline is present at a concentration of atleast 0.1 weight percent and the phenylephrine is present at aconcentration of at least 0.25 weight percent.

In one embodiment the oxymetazoline is present at a concentration of 0.1weight percent and the phenylephrine is present at a concentration of0.25 weight percent.

In one embodiment the composition further comprises an antioxidant.

In one embodiment the composition further comprises vitamin A.

In one embodiment the composition further comprises an astringent.

In one embodiment the composition further comprises a lubricant.

In one embodiment the composition further comprises a blue dye.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a series of three photographic images of the face of a subjectbefore (top), 30 minutes after (middle), and 90 minutes after (bottom)topical administration of a single drop of oxymetazoline 0.1% to eacheye.

FIG. 2 is a series of three photographic images of the face of a subjectbefore (top), and 25 minutes (middle) and three and one-half hours(bottom) following topical administration of a single drop ofoxymetazoline 0.1% to the subject's left eye.

FIG. 3A is a baseline visual field map of a ptotic eye in a patient withsignificant ptosis of one eye. Open ovals represent seen spots. Closedovals represent not seen spots.

FIG. 3B is a visual field map of the same ptotic eye as in FIG. 3A,measured 2 hours and 20 minutes following administration of a singledrop of 0.1% oxymetazoline to that eye.

FIG. 3C is a visual field map of the same ptotic eye as in FIG. 3A andFIG. 3B, measured 4 hours following administration of a single drop of0.1% oxymetazoline to that eye.

DETAILED DESCRIPTION OF THE INVENTION

The upper eyelids are normally lifted by contraction of the levatorpalpebrae superioris (levator) and Müller's (Mueller's) muscles. Ptosiscreates a tired-looking appearance that can be cosmetically undesired;in more severe instances ptosis can interfere with vision in theaffected eye(s).

In addition to fatigue and age-related weakening of the levator andMüller's muscles as underlying causes of ptosis, there are a number ofother conditions recognized to cause ptosis. For example, ptosis mayalso be due to a myogenic, neurogenic, aponeurotic, mechanical, ortraumatic cause; it usually occurs isolated, but it may be associatedwith various other conditions, like hereditary, immunological, ordegenerative disorders, tumors, and infections.

Myogenic causes of ptosis can include diseases which may cause weaknessin muscles or nerve damage, such as myasthenia gravis and chronicprogressive external ophthalmoplegia. Dystrophy or dysgenesis of thelevator and/or Müller's muscles are the most common causes of congenitalptosis.

Ptosis may be caused by damage to the third cranial nerve (oculomotornerve) which controls the muscles which raise the upper eyelid.Congenital neurogenic ptosis is believed to be caused by Horner syndrome(also known as Horner's syndrome), in which a mild ptosis due to theparesis of the Müller muscle may be associated with ipsilateral miosis(pupillary constriction) and anhidrosis. Acquired Horner syndrome mayresult after trauma, neoplastic insult, or even vascular disease.

Acquired ptosis is commonly caused by aponeurotic ptosis. This can occuras a result of senescence, dehiscence or disinsertion of the levatoraponeurosis. Moreover, chronic inflammation or intraocular surgery canlead to the same effect.

Ptosis due to trauma can ensue after an eyelid laceration withtransection of the upper eyelid elevator muscles or disruption of theneural input.

Other causes of ptosis include eyelid neoplasms, neurofibromas, or thecicatrization after inflammation or surgery. Mild ptosis may occur withaging.

Compositions and methods of the invention may be particularly useful fortreating ptosis in subjects with functional, or at least partiallyfunctional, levator and/or Müller's muscles and their respectiveaponeuroses.

The present inventor has surprisingly found, through a process ofevaluating a number of agents over a range of concentrations of suchagents, that certain alpha adrenergic agonists, including in particularoxymetazoline 0.1 percent, provide highly effective treatment of ptosis,lasting for several hours, following topical administration of just asingle drop of such agent to an affected eye.

An aspect of the invention is a method for treating ptosis in a subject.The method includes the step of administering an effective amount ofoxymetazoline to the exterior surface of an eye of a subject in need ofsuch treatment. As used herein, “treating” means reducing, even if onlytemporarily, the severity of a condition or disease in a subject havingsuch condition or disease. In one embodiment the reducing iseliminating, even if only temporarily. For example, ptosis in a subjectis said to be treated in accordance with the method if the ptosis isreduced or eliminated, even if only temporarily. Also as used herein, a“subject” refers to a living mammal. In one embodiment the subject is ahuman. A “subject in need of such treatment” is a subject having acondition in need of treatment. For example, in the context of thisaspect of the invention, a subject in need of such treatment is asubject that has ptosis of at least one eyelid.

A subject has ptosis when at least the left or the right upper eyelid issubjectively or objectively ptotic compared to historical control and/orthe other eye. In one embodiment both the left and the right uppereyelid are ptotic, although not necessarily to the same degree.Historical control can be provided in the form of a photographic image,for example.

In one embodiment a subject is said to have ptosis when at least theleft or the right upper eyelid is ptotic by at least one millimeter (mm)compared to historical control and/or the other eye. Such measurementinvolves measuring the widest separation of the upper and lower lids inthe sagittal plane, typically but not necessarily across the center ofthe pupil, with the subject at rest, i.e., without any conscious efforton the part of the subject to widen the lids. In one embodiment themeasurement is made on the eye or eyes of a living subject. In oneembodiment the measurement is made or based on a photographic image ofthe subject's eye or eyes.

Oxymetazoline is3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol,CAS number 1491-59-4. It was developed from xylometazoline at E. MerckDarmstadt by Fruhstorfer in 1961 (German Patent 1,117,588).

Oxymetazoline is a well known potent alpha adrenergic agonist that findsuse as a vasoconstrictor. It has been used in the form of itshydrochloride salt as the principal active agent in topical nasaldecongestants such as Afrin (Schering Plough). Afrin provides 12-hourrelief for sinus congestion and was first sold as a prescriptionmedication in 1966. It has been available as an over-the-counter drugsince 1975.

Oxymetazoline has also been used to treat eye redness due to minorirritation (marketed in the form of eye drops as Visine® L.R.® (Johnson& Johnson) and Ocuclear® (Schering)). Each of these eye dropformulations contains 0.025 percent oxymetazoline hydrochloride (HCl) asthe active agent. Indications for Visine® L.R.® and Ocuclear® areredness due to minor eye irritation, and burning, irritation, anddryness of the eye caused by wind, sun, and other minor irritants.Ocuclear is also marketed for use in the treatment of acute allergicconjunctivitis and non-infectious conjunctivitis.

Ocular use of oxymetazoline has been described in the literature. Duzmanet al. reported the characterization of ocularly administeredoxymetazoline hydrochloride at 0.01 percent, 0.025 percent, and 0.05percent for the treatment of hyperemia (redness). Duzman et al. (1983)Arch Ophthalmol 101:1122-6. In this report, the authors concluded thatthe optimal concentration of oyxmetazoline was 0.025 percent.

In a study of safety and tolerance of ophthalmic solution for possibleuse in treating allergic conjunctivitis, Samson et al. concluded that0.025 percent oxymetazoline was well tolerated and subjects preferredformulation in boric acid rather than phosphate buffer. Samson et al.(1980) Pharmatherapeutica 2:347-52.

Additional studies have examined the use of oxymetazoline 0.004 percentto 0.025 percent for the treatment of benign red eye (Vajpayee et al.(1986) Indian J Ophthalmol 34:33-6) and allergic and non-infectiousconjunctivitis (Fox et al. (1979) J Int Med Res 7:528-30; Breakly et al.(1980) Pharmatherapeutica 2:353-6; Duzman et al. (1986) Ann Ophthalmol18:28-31; and Xuan et al. (1997) J Ocul Pharmacol Ther 13:363-7).

U.S. Pat. No. 6,730,691 to Galin discloses the topical application ofophthalmic solutions containing one or more alpha adrenergic blockingagents to inhibit undesirable visual anomalies, such as photophobia,glare, secondary images, and haloing, in individuals who have undergonerefractive eye surgery. In one embodiment the solution includes ananti-irritant agent selected from the group consisting of naphthazoline,oxymetazoline, and tetrahydrozaline. In one embodiment suchanti-irritant is disclosed to be included in a concentration of fromabout 0.025 percent by weight to about 0.1 percent by weight.

U.S. Pat. No. 7,022,740 to Mackles discloses lubricious ophthalmicsolutions consisting essentially of an aqueous solution of a monographedpolyol (e.g., polyvinyl alcohol), borate, a monographed polysorbate(e.g., monolaurate, monopalmitate, monostearate), preservative, andbuffer. Mackles teaches that pharmacologically active substances solublewithin such solution can be formulated together with the solution,including ophthalmic vasoconstrictors such as ephedrine HCl, naphazolineHCl, phenylephrine HCl, tetrahydrozoline HCl, and oxymetazoline HCl, thelatter at 0.05 percent.

US Patent Application Publication No. 2007/0264318 by Chapin et al.discloses compositions and methods for the treatment and prevention ofeyelid swelling. The compositions and methods are based on osmoticallyactive agent and/or a vasoconstrictor and/or an astringent. In someembodiments the composition is disclosed to include a vasoconstrictor,including nephazoline, oxymetazoline, phenylephrine, or tetrahydrozine.Eyelid swelling was measured using 3D scanning technology.

An effective amount of oxymetazoline is administered to the exteriorsurface of an eye. As used herein, an “effective amount” is an amountthat is sufficient to achieve a desired biological result. For example,an effective amount of oxymetazoline is an amount of oxymetazoline thatis sufficient to treat ptosis in a subject having ptosis. The effectiveamount can vary depending on such factors as the disease or conditionbeing treated, or the severity of the disease or condition. One of skillin the art may empirically determine an effective amount of a particularagent without necessitating undue experimentation.

The effective amount is administered to the eye or eyes intended fortreatment. For example, if the left eyelid is ptotic, the effectiveamount of oxymetazoline is administered to the left eye.

Administering can be accomplished using any suitable method for topicaladministration of a pharmaceutical agent to the exterior surface of aneye. In one embodiment the administering involves delivering the agentin dropwise fashion to the eye. One or more drops can be administered tothe eye. In one embodiment, a single drop is administered to the eye.

The exterior surface of an eye refers to any portion of the surface ofan eye that is normally visible and/or accessible within the palpebralfissure, e.g., the surface of the eye that is normally exposed and/oraccessible between the upper and lower eyelids. This surface can includeany or all of the following structures: the cornea, the conjunctiva, andthe tear sac. In one embodiment this surface is accessible withoutmanual manipulation of the upper or lower eyelids to permitadministration. In one embodiment this surface is made accessible bymanually opening or widening the palpebral fissure to permit or assistin administration.

In one embodiment the method results in at least a 0.5 mm increase inthe vertical separation of the upper and lower lids of the eye. Theincrease is the difference between the separation of the lids beforetreatment and separation following treatment. The vertical separationcan be measured using any suitable method. In one embodiment measuringinvolves measuring the widest separation of the upper and lower lids inthe sagittal plane, typically but not necessarily across the center ofthe pupil, with the subject at rest, i.e., without any conscious efforton the part of the subject to widen the lids. The measurement may beaided by asking the subject to look at a distant fixation light orpoint. In one embodiment the measurement is made on the eye or eyes of aliving subject, for example using a fine point metric ruler. In oneembodiment the measurement is made or based on a photographic image ofthe subject's eye or eyes, for example using a fine point metric ruleror a magnifier with a metric graticule (Edmund Scentific, Paramus,N.J.). In one embodiment the method results in at least a 1 mm increasein the vertical separation of the upper and lower lids of the eye.

The increase is the difference between the separation of the lids beforetreatment and the separation of the lids following treatment. Forexample, if the separation is 8 mm before treatment and the separationis 10 mm following treatment, the increase is 2 mm. Since there may besome time lag in reaching the maximum effect, in one embodiment theincrease is the maximum increase achieved following administration ofthe active agent. For example, if the separation is 8 mm beforetreatment, 9 mm immediately after treatment, 10 mm 30 minutes aftertreatment, and 8 mm 16 hours after treatment, the increase is 2 mm.

Alternatively or in addition, in one embodiment the method results in atleast a 5 percent increase in the vertical separation of the upper andlower lids of the eye. The vertical separation can be measured asdescribed above, and then the percent increase calculated as:[(D_(after)−D_(before))/D_(before)]×100%, where D_(after) is thevertical separation of the lids following treatment and D_(before) isthe vertical separation of the lids before treatment. For example, ifthe separation is 8 mm before treatment and the separation is 10 mmfollowing treatment, the percent increase is [(10−8)/8]×100%=25%. Sincethere may be some time lag in reaching the maximum effect, in oneembodiment the percent increase is the maximum percent increase achievedfollowing administration of the active agent. For example, if theseparation is 8 mm before treatment, 9 mm immediately after treatment,10 mm 30 minutes after treatment, and 8 mm 16 hours after treatment, thepercent increase is [(10−8)/8]×100%=25%. In one embodiment the methodresults in at least a 10 percent increase in the vertical separation ofthe upper and lower lids of the eye. In one embodiment the methodresults in at least a 20 percent increase in the vertical separation ofthe upper and lower lids of the eye.

In one embodiment the oxymetazoline is formulated as a pharmaceuticalcomposition comprising at least 0.05 weight percent oxymetazoline in anophthalmologically acceptable carrier. In one embodiment theoxymetazoline is formulated as a pharmaceutical composition comprisingat least 0.1 weight percent oxymetazoline in an ophthalmologicallyacceptable carrier. The invention further embraces embodiments in whicha higher weight percentage of oxymetazoline is used, for example, up toand including 1.0 weight percent oxymetazoline. Accordingly, in variousembodiments the oxymetazoline may be present at a concentration of 0.05,0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 weight percent, orany concentration therebetween. In one embodiment the oxymetazoline ispresent at a concentration of 0.1 weight percent.

As used herein, an “ophthalmologically acceptable carrier” is anypharmaceutically acceptable carrier that is suitable for topicaladministration to the eye.

In one embodiment the oxymetazoline is provided as a pharmaceuticallyacceptable salt of oxymetazoline. The term “pharmaceutically acceptablesalts” is art-recognized, and refers to relatively non-toxic, inorganicand organic acid addition salts of compositions of the present inventionor any components thereof, including without limitation, therapeuticagents, excipients, other materials and the like. Examples ofpharmaceutically acceptable salts include those derived from mineralacids, such as hydrochloric acid and sulfuric acid, and those derivedfrom organic acids, such as ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like. Examples of suitable inorganicbases for the formation of salts include but are not limited to thehydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium,potassium, calcium, magnesium, aluminum, zinc and the like. Salts mayalso be formed with suitable organic bases, including those that arenon-toxic and strong enough to form such salts. For purposes ofillustration, the class of such organic bases may include mono-, di-,and trialkylamines, such as methylamine, dimethylamine, andtriethylamine; mono-, di- or trihydroxyalkylamines such as mono-, di-,and triethanolamine; amino acids, such as arginine and lysine;guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine;N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine;(trihydroxymethyl)aminoethane; and the like. See, for example, Berge etal. (1977) J. Pharm. Sci. 66:1-19.

In one embodiment the pharmaceutically acceptable salt of oxymetazolineis oxymetazoline hydrochloride.

When the oxymetazoline is provided as a pharmaceutically acceptablesalt, in one embodiment the weight percent oxymetazoline can be based onthe oxymetazoline component alone. Alternatively, when the oxymetazolineis provided as a pharmaceutically acceptable salt, the weight percentoxymetazoline can be based on the oxymetazoline salt.

In one embodiment the administering is administering as a single drop.The drop can be dispensed, for example, from a suitably constructedsqueeze bottle or from a dropper. A single drop typically has a volumeof about 0.1 to 0.35 milliliters (mL).

In one embodiment the administering is performed by the subject. In oneembodiment the administering is performed by an individual other thanthe subject, e.g., by a health care provider, a parent, or a spouse.

In one embodiment the administering is administering at least oncedaily. The invention contemplates administration once, twice, threetimes, and up to four times in any given 24 hour period. Foradministration more than once daily, the administering can be performedover equal periods, for example every twelve hours, or unequal periods,for example at 7 a.m. and 3 p.m. (rather than 7 a.m. and 7 p.m.). In oneembodiment the administering is administering once daily.

Certain subjects may be excluded from the methods of the invention. Inone embodiment the subject does not have an allergic ocular conditioncalling for treatment of the eye with oxymetazoline. In one embodimentthe subject does not have eyelid swelling. In one embodiment the subjecthas not undergone refractive eye surgery. In one embodiment the subjectdoes not have an allergic ocular condition calling for treatment of theeye with oxymetazoline and the subject does not have eyelid swelling. Inone embodiment the subject does not have an allergic ocular conditioncalling for treatment of the eye with oxymetazoline and the subject hasnot undergone refractive eye surgery. In one embodiment the subject doesnot have eyelid swelling and the subject has not undergone refractiveeye surgery. In one embodiment the subject does not have an allergicocular condition calling for treatment of the eye with oxymetazoline,does not have eyelid swelling, and has not undergone refractive eyesurgery. Alternatively or in addition, in certain embodiments thesubject does not have acute allergic conjunctivitis or non-infectiousconjunctivitis.

An aspect of the invention is a method for treating ptosis in a subject.The method includes the step of administering an effective amount of along-acting alpha adrenergic agonist and an effective amount of ashort-acting alpha adrenergic agonist to the exterior surface of an eyeof a subject in need of such treatment. As used herein, a “long-actingalpha adrenergic agonist” is an alpha adrenergic agonist with a systemichalf-life in normal adult humans of greater than three hours.Long-acting alpha adrenergic agonists include, without limitation,oxymetazoline, methoxamine, naphazoline, tetrahydrozoline,xylometazoline, and apraclonidine (also known as Iopidine®). The longestacting of these agents is oxymetazoline, with a reported half-life of 5to 6 hours. In one embodiment the long-acting alpha adrenergic agonistis a pharmaceutically acceptable salt of the long-acting alphaadrenergic agonist. In one embodiment the long-acting alpha adrenergicagonist is oxymetazoline or a pharmaceutically acceptable salt thereof,e.g., oxymetazoline hydrochloride.

As used herein, a “short-acting alpha adrenergic agonist” is an alphaadrenergic agonist with a systemic half-life in normal adult humans ofless than or equal to three hours. Short-acting alpha adrenergicagonists include, without limitation, phenylephrine and brimonidine. Inone embodiment the short-acting alpha adrenergic agonist is apharmaceutically acceptable salt of the short-acting alpha adrenergicagonist. In one embodiment the short-acting alpha adrenergic agonist isphenylephrine or a pharmaceutically acceptable salt thereof, e.g.,phenylephrine hydrochloride.

Phenylephrine is frequently used in pre-surgical evaluation of ptosis.Typically, to predict what result might be expected from surgicaltreatment of ptosis, a single drop of phenylephrine 2.5% is placed inthe affected eye. There is a rapid (nearly immediate) response withlifting of the lid. However, this pharmacological response lasts forless than one hour, and it may include dilation of the pupil of thetreated eye.

As disclosed in Example 8 herein, it was found that a combination ofoxymetazoline, e.g., 0.1%, together with phenylephrine, e.g., 0.25%,unexpectedly acts synergistically in the treatment of ptosis. The effectof the combination is dramatically greater than not only the effect ofeither agent alone but also the sum of the effects of each agent alone.This synergistic effect was found to occur even with a combinationincluding an amount of phenylephrine that induces, at most, only aminimal amount of mydriasis, i.e., clinically insignificant mydriasis.

In one embodiment the long-acting alpha adrenergic agonist is providedas a pharmaceutical composition comprising at least 0.1 weight percentoxymetazoline and the short-acting alpha adrenergic agonist is providedas a pharmaceutical composition comprising at least 0.15 weight percentphenylephrine. In one embodiment the long-acting alpha adrenergicagonist is provided as a pharmaceutical composition comprising at least0.1 weight percent oxymetazoline and the short-acting alpha adrenergicagonist is provided as a pharmaceutical composition comprising at least0.25 weight percent phenylephrine. In one embodiment the long-actingalpha adrenergic agonist is provided as a pharmaceutical compositioncomprising 0.1 weight percent oxymetazoline and the short-acting alphaadrenergic agonist is provided as a pharmaceutical compositioncomprising 0.25 weight percent phenylephrine.

In one embodiment oxymetazoline is formulated together withphenylephrine as a pharmaceutical composition comprising at least 0.05weight percent oxymetazoline and at least 0.15 weight percentphenylephrine in an ophthalmologically acceptable carrier.

In one embodiment oxymetazoline is formulated together withphenylephrine as a pharmaceutical composition comprising at least 0.1weight percent oxymetazoline and at least 0.15 percent phenylephrine inan ophthalmologically acceptable carrier. In one embodiment theoxymetazoline is formulated together with the phenylephrine as apharmaceutical composition comprising at least 0.1 weight percentoxymetazoline and at least 0.25 weight percent phenylephrine in anophthalmologically acceptable carrier. In one embodiment theoxymetazoline is formulated together with the phenylephrine as apharmaceutical composition comprising 0.1 weight percent oxymetazolineand 0.25 weight percent phenylephrine in an ophthalmologicallyacceptable carrier.

In one embodiment the oxymetazoline is present at a concentration of atleast 0.1 weight percent. In various embodiments the oxymetazoline maybe present at a concentration of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, or 1.0 weight percent, or any concentration therebetween. In oneembodiment the oxymetazoline is present at a concentration of 0.1 weightpercent.

In one embodiment the phenylephrine is present at a concentration of0.15 to 1.5 weight percent. Accordingly, in various embodiments thephenylephrine can be present at a concentration of 0.15, 0.2, 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 weight percent,or any concentration therebetween. In one embodiment the phenylephrineis present at a concentration of 0.25 weight percent.

An aspect of the invention is a pharmaceutical composition, comprisingoxymetazoline, a short-acting alpha adrenergic agonist, and apharmaceutically acceptable carrier, formulated for topical ophthalmicuse. In one embodiment the oxymetazoline is provided as apharmaceutically acceptable salt, e.g., oxymetazoline hydrochloride. Inone embodiment the short-acting alpha adrenergic agonist isphenylephrine or a pharmaceutically acceptable salt thereof, e.g.,phenylephrine hydrochloride.

In one embodiment the oxymetazoline is present at a concentration of atleast 0.1 weight percent. In various embodiments the oxymetazoline maybe present at a concentration of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, or 1.0 weight percent, or any concentration therebetween. In oneembodiment the oxymetazoline is present at a concentration of 0.1 weightpercent.

In one embodiment the phenylephrine is present at a concentration of0.15 to 1.5 weight percent. Accordingly, in various embodiments thephenylephrine can be present at a concentration of 0.15, 0.2, 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 weight percent,or any concentration therebetween. In one embodiment the phenylephrineis present at a concentration of 0.25 weight percent.

In one embodiment the oxymetazoline is present at a concentration of atleast 0.1 weight percent and the phenylephrine is present at aconcentration of at least 0.25 weight percent.

In one embodiment the oxymetazoline is present at a concentration of 0.1weight percent and the phenylephrine is present at a concentration of0.25 weight percent.

The pharmaceutical composition optionally can include at least oneadditional active agent. For example, in one embodiment thepharmaceutical composition further includes an anti-oxidant. Anantioxidant is a molecule capable of inhibiting the oxidation of othermolecules. Oxidation is a chemical reaction that transfers electronsfrom a substance to an oxidizing agent. Oxidation reactions can producefree radicals. In turn, these radicals can start chain reactions thatdamage cells. Antioxidants terminate these chain reactions by removingfree radical intermediates, and inhibit other oxidation reactions. Theydo this by being oxidized themselves, so antioxidants are often reducingagents such as thiols, ascorbic acid or polyphenols. Antioxidants areclassified into two broad divisions, depending on whether they aresoluble in water (hydrophilic) or in lipids (hydrophobic). In general,water-soluble antioxidants react with oxidants in the cell cytosol andthe blood plasma, while lipid-soluble antioxidants protect cellmembranes from lipid peroxidation. Water-soluble antioxidants include,without limitation, ascorbic acid (vitamin C), glutathione, lipoic acid,and uric acid. Lipid-soluble antioxidants include, without limitation,carotenes (e.g., alpha-carotene, beta-carotene), alpha-tocopherol(vitamin E), and ubiquinol (coenzyme Q).

In one embodiment the antioxidant is N-acetylcarnosine. In oneembodiment the antioxidant is sodium metabisulfite.

As a further example, in one embodiment the pharmaceutical compositionfurther includes vitamin A (retinol). When converted to the retinal(retinaldehyde) form, vitamin A is essential for vision, and whenconverted to retinoic acid, is essential for skin health and bonegrowth. These chemical compounds are collectively known as retinoids,and possess the structural motif of all-trans retinol as a commonfeature in their structure. Topical vitamin A, for example in the formof eye drops containing retinyl palmitate 0.05 percent, has beenreported to be effective treatment for dry eye (also known askeratoconjunctivitis sicca, xerophthalmia, and dry eye syndrome). Kim etal. (2009) Am J Ophthalmol 147:206-13. Vitamin A has also beenformulated at a strength of 50,000 units/mL for ophthalmic use.

In one embodiment the pharmaceutical composition further includes anastringent. Astringents include, but are not limited to, witch hazel,zinc sulfate, silver sulfate, plant tannins, oak bark extract, birdcherry extract, and natural flavinoids. In one embodiment the astringentis witch hazel, which is an astringent produced from the leaves and barkof the North American Witch Hazel shrub (Hamamelis virginiana), whichgrows naturally from Nova Scotia west to Ontario, Canada, and south toFlorida and Texas in the United States. Witch hazel is readily availablefrom a number of commercial suppliers, including Dickinson's and HenryThayer.

The pharmaceutical composition optionally can include at least oneadditional inert or non-active agent. In one embodiment thepharmaceutical composition further includes a lubricant. Ocularlubricants are solutions, gels, or ointments formulated to moisturizethe eyes. Included among ocular lubricants are artificial tears, such asare available from any of a variety of commercial suppliers. In certainembodiments, such lubricants typically may include an aqueous solutionof a polyalcohol (polyol) such as polyvinyl alcohol, borate, and abuffer. In certain embodiment, ocular lubricants may include whitepetrolatum and mineral oil.

In one embodiment the pharmaceutical composition further includes a bluedye, e.g., methylene blue. The blue dye confers a lightening orwhitening effect on the sclera, thereby making “tired eyes” appear lesstired.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andrefers to, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting any supplement or composition, or component thereof, fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the supplement and not injurious to thepatient. In certain embodiments, a pharmaceutically acceptable carrieris non-pyrogenic. Some examples of materials which may serve aspharmaceutically acceptable carriers include: pyrogen-free water;aqueous solutions, suspensions, and ointments; isotonic saline; Ringer'ssolution; phosphate buffer solutions; borate solutions; sugars, such aslactose, glucose and sucrose; starches, such as corn starch and potatostarch; cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients, such as cocoa butter and suppositorywaxes; oils, such as peanut oil, cottonseed oil, sunflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols, such as propyleneglycol; polyols, such as glycerin, sorbitol, mannitol and polyethyleneglycol; esters, such as ethyl oleate and ethyl laurate; agar; bufferingagents, such as magnesium hydroxide and aluminum hydroxide; alginicacid; ethyl alcohol; and other non-toxic compatible substances employedin pharmaceutical formulations.

Featured are novel topical pharmaceutical compositions comprising aneffective amount of one or more active agents in a pharmaceuticallyacceptable carrier for the treatment and prevention of ptosis and/or“tired eyes”. Such formulations provide a comfortable formulation wheninstilled in the eye. The one or more active agents may include, but arenot limited to, alpha adrenergic agonists and, optionally, one or moreastringent agents, antioxidants, vitamin A, and any combination thereof.

In one embodiment, the pharmaceutical compositions of the inventioncomprise one or more active ingredients formulated in an aqueoussolution. Alternatively or in addition, the pharmaceutical compositionsmay be formulated for topical administration as solutions, suspensions,oils, viscous or semi-viscous gels, emulsions, liposomes, lotions,ointments, creams, gels, salves, powders, and sustained or slow release,or other types of solid or semi-solid compositions, includingformulations described in U.S. Pat. No. 6,806,364. The compositions mayalso be topically administered in a sprayable form.

In one embodiment the pharmaceutical compositions includes a tearsubstitute. A variety of tear substitutes are known in the art,including but not limited to: polyols such as, glycerol, glycerin,polyethylene glycol 300, polyethylene glycol 400, polysorbate 80,propylene glycol, and ethylene glycol, polyvinyl alcohol, povidone, andpolyvinylpyrrolidone; cellulose derivatives such hydroxypropylmethylcellulose (also known as hypromellose), carboxy methylcellulosesodium, hydroxypropyl cellulose, hydroxyethyl cellulose, andmethylcellulose; dextrans such as dextran 70; water soluble proteinssuch as gelatin; carbomers such as carbomer 934P, carbomer 941, carbomer940 and carbomer 974P; and gums such as HP-guar. Many such tearsubstitutes are commercially available, which include, but are notlimited to cellulose esters such as Bion Tears®, Celluvisct, Gentealt,OccuCoatt, Refresh®, Teargen II®, Tears Naturale®, Tears Naturale 118®,Tears Naturale Free®, and TheraTears®; and polyvinyl alcohols such asAkwa Tears®, HypoTears®, Moisture Eyes®, Murine Lubricating®, and VisineTears®. In other embodiments, the tear substitute is that which isdescribed in U.S. Pat. No. 6,806,364, which is expressly incorporated byreference herein in its entirety. The formulation described in U.S. Pat.No. 6,806,364 contains 0.2 to 2.5 (e.g., 0.5 to 0.8) percent by weightof hydroxypropyl methylcellulose, 0.045 to 0.065 (e.g., 0.05 to 0.06)percent by weight a calcium salt, and 0.14 to 1.4 (e.g., 0.3 to 1.2)percent by weight a phosphate salt. The formulation described in U.S.Pat. No. 6,806,364 has a viscosity of 20 to 150 (e.g., 50 to 90)centipoise and is buffered to a pH 5.5 to 8.5 (e.g., 6 to 8) with aphosphate salt or other suitable salts. It may further contain one ormore of the following ingredients: 0.5 to 1.0 percent by weightglycerol, 0.5 to 1.0 percent by weight propyleneglycerol, 0.005 to 0.05percent by weight glycine, 0.006 to 0.08 percent by weight sodiumborate, 0.025 to 0.10 percent by weight magnesium chloride, and 0.001 to0.01 percent by weight zinc chloride.

Tear substitutes may also be comprised of paraffins, such as thecommercially available Lacri-Lube® ointments. Other commerciallyavailable ointments that are used as tear substitutes include LubrifreshPM®, Moisture Eyes PM®, and Refresh PM®.

The pharmaceutical compositions may be formulated for topicaladministration as solutions, suspensions, oils, viscous or semi-viscousgels, emulsions, liposomes, lotions, ointments, creams, gels, salves,powders, and sustained or slow release, or other types of solid orsemi-solid compositions, including formulations described in U.S. Pat.No. 6,806,364. The composition may also be topically administered in asprayable form.

Any of a variety of carriers may be used in the formulations of thepresent invention, including water, mixtures of water and water-misciblesolvents, such as, but not limited to, C1- to C7-alkanols, vegetableoils or mineral oils comprising from 0.5 to 5% non-toxic water-solublepolymers, natural products, such as gelatin, alginates, pectins,tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia,starch derivatives, such as starch acetate and hydroxypropyl starch, andalso other synthetic products, such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid, such as neutral Carbopol, ormixtures of those polymers. The concentration of the carrier is,typically, from 1 to 100,000 times the concentration of the activeingredient.

Additional ingredients that may be included in the formulation includetonicity enhancers, preservatives, solubilizers, non-toxic excipients,demulcents, sequestering agents, pH adjusting agents, co-solvents andviscosity building agents.

For the adjustment of the pH, preferably to a physiological pH, buffersmay be especially useful. The pH of the present solutions should bemaintained within the range of 4.0 to 8.0, more preferably about 4.0 to6.0, more preferably about 6.5 to 7.8. Suitable buffers may be added,such as, but not limited to, boric acid, sodium borate, potassiumcitrate, citric acid, sodium bicarbonate, TRIS, and various mixedphosphate buffers (including combinations of Na₂HPO₄, NaH₂PO₄, andKH₂PO₄) and mixtures thereof. Generally, buffers will be used in amountsranging from about 0.05 to 2.5 percent by weight, and preferably, from0.1 to 1.5 percent.

Tonicity is adjusted, if needed, typically by tonicity enhancing agents.Such agents may, for example, be of ionic and/or non-ionic type.Examples of ionic tonicity enhancers include, but are not limited to,alkali metal or alkaline earth metal halides, such as, for example,CaCl₂), KBr, KCl, LiCl, NaI, NaBr, NaCl, Na₂SO₄, or boric acid.Non-ionic tonicity enhancing agents are, for example, urea, glycerol,sorbitol, mannitol, propylene glycol, or dextrose. These agents may alsoserve as the active agents in certain embodiments. The aqueous solutionsof the present invention are typically adjusted with tonicity agents toapproximate the osmotic pressure of normal lachrymal fluids which isequivalent to a 0.9% solution of sodium chloride or a 2.5% solution ofglycerol. An osmolality of about 225 to 400 mOsm/kg is preferred, morepreferably 280 to 320 mOsm.

In certain embodiments, the topical formulations additionally comprise apreservative. A preservative may typically be selected from a quaternaryammonium compound such as benzalkonium chloride (N-benzyl-N—(C8-C18alkyl)-N,N-dimethylammonium chloride), benzoxonium chloride, or thelike. Examples of preservatives different from quaternary ammonium saltsare alkyl-mercury salts of thiosalicylic acid, such as, for example,thimerosal (also known as thiomersal), phenylmercuric nitrate,phenylmercuric acetate or phenylmercuric borate, sodium perborate,sodium chlorite, parabens, such as, for example, methylparaben orpropylparaben, alcohols, such as, for example, chlorobutanol, benzylalcohol or phenyl ethanol, guanidine derivatives, such as, for example,chlorohexidine or polyhexamethylene biguanide, sodium perborate, Germal®II or sorbic acid. Preferred preservatives are quaternary ammoniumcompounds, in particular benzalkonium chloride or its derivative such asPolyquad (see U.S. Pat. No. 4,407,791), alkyl-mercury salts andparabens. Where appropriate, a sufficient amount of preservative isadded to the ophthalmic composition to ensure protection againstsecondary contaminations during use caused by bacteria and fungi.

In another embodiment, the topical formulations of this invention do notinclude a preservative. Such formulations would be useful for patientswho wear contact lenses, or those who use several topical ophthalmicdrops and/or those with an already compromised ocular surface (e.g. dryeye) wherein limiting exposure to a preservative may be desirable.

The topical formulation may additionally include a solubilizer, inparticular if the active or the inactive ingredients tend to form asuspension or an emulsion. A solubilizer suitable for an above-concernedcomposition is for example selected from the group consisting oftyloxapol, fatty acid glycerol polyethylene glycol esters, fatty acidpolyethylene glycol esters, polyethylene glycols, glycerol ethers, acyclodextrin (for example alpha-, beta- or gamma-cyclodextrin, e.g.alkylated, hydroxyalkylated, carboxyalkylated oralkyloxycarbonyl-alkylated derivatives, or mono- or diglycosyl-alpha-,beta- or gamma-cyclodextrin, mono- or dimaltosyl-alpha-, beta- orgamma-cyclodextrin, or panosyl-cyclodextrin), polysorbate 20,polysorbate 80, or mixtures of those compounds. In one embodiment thesolubilizer is a reaction product of castor oil and ethylene oxide, forexample the commercial products Cremophor EL® or Cremophor RH400.Reaction products of castor oil and ethylene oxide have proved to beparticularly good solubilizers that are tolerated extremely well by theeye. Another preferred solubilizer is selected from tyloxapol and from acyclodextrin. The concentration used depends especially on theconcentration of the active ingredient. The amount added is typicallysufficient to solubilize the active ingredient. For example, in oneembodiment the concentration of the solubilizer is from 0.1 to 5000times the concentration of the active ingredient.

The formulations may comprise further non-toxic excipients, such as, forexample, emulsifiers, wetting agents or fillers, such as, for example,the polyethylene glycols designated 200, 300, 400 and 600, or Carbowaxdesignated 1000, 1500, 4000, 6000 and 10000. The amount and type ofexcipient added is in accordance with the particular requirements and isgenerally in the range of from approximately 0.0001 to approximately 90%by weight.

Other compounds may also be added to the formulations of the presentinvention to increase the viscosity of the carrier. Examples ofviscosity enhancing agents include, but are not limited to:polysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily; vinyl polymers; and acrylic acid polymers.

The dosage of any compound of the present invention will vary dependingon the symptoms, age, and other physical characteristics of the patient,the nature and severity of the disorder to be treated or prevented, thedegree of comfort desired, the route of administration, and the form ofthe medicament. Any of the subject formulations may be administered in asingle dose or in divided doses. Dosages for the formulations of thepresent invention may be readily determined by techniques known to thoseof skill in the art or as taught herein.

An effective dose or amount, and any possible effects on the timing ofadministration of the formulation, may need to be identified for anyparticular formulation of the present invention. This may beaccomplished by routine experiment as described herein. Theeffectiveness of any formulation and method of treatment or preventionmay be assessed by administering the formulation and assessing theeffect of the administration by measuring one or more indices associatedwith the efficacy of the agent and with the degree of comfort to thepatient, as described herein, and comparing the post-treatment values ofthese indices to the values of the same indices prior to treatment or bycomparing the post-treatment values of these indices to the values ofthe same indices using a different formulation.

The precise time of administration and amount of any particularformulation that will yield the most effective treatment in a givenpatient will depend upon the activity, pharmacokinetics, andbioavailability of a particular compound, physiological condition of thepatient (including age, sex, disease type and stage, general physicalcondition, responsiveness to a given dosage and type of medication), andthe like. The guidelines presented herein may be used to optimize thetreatment, e.g., determining the optimum time and/or amount ofadministration, which will require no more than routine experimentationconsisting of monitoring the subject and adjusting the dosage and/ortiming.

The combined use of several agents formulated into the compositions ofthe present invention may reduce the required dosage for any individualcomponent because the onset and duration of effect of the differentcomponents may be complimentary or even synergistic. In such combinedtherapy, the different agents may be delivered together or separately,and simultaneously or at different times within the day.

The formulations of the present invention may be packaged as either asingle-dose product or a multi-dose product. The single-dose product issterile prior to opening of the package and all of the composition inthe package is intended to be consumed in a single application to one orboth eyes of a patient. The use of an antimicrobial preservative tomaintain the sterility of the composition after the package is opened isoptional.

Multi-dose products are also sterile prior to opening of the package.However, because the container for the composition may be opened manytimes before all of the composition in the container is consumed, themulti-dose products typically have sufficient antimicrobial activity toensure that the compositions will not become contaminated by microbes asa result of the repeated opening and handling of the container. Thelevel of antimicrobial activity required for this purpose is well knownto those skilled in the art, and is specified in official publications,such as the United States Pharmacopoeia (“USP”), other publications bythe Food and Drug Administration, and corresponding publications inother countries. Detailed descriptions of the specifications forpreservation of ophthalmic pharmaceutical products against microbialcontamination and the procedures for evaluating the preservativeefficacy of specific formulations are provided in those publications. Inthe United States, preservative efficacy standards are generallyreferred to as the “USP PET” requirements. (The acronym “PET” stands for“preservative efficacy testing”.)

The use of a single-dose packaging arrangement eliminates the need foran antimicrobial preservative in the compositions, which is asignificant advantage from a medical perspective, because conventionalantimicrobial agents utilized to preserve ophthalmic compositions (e.g.,benzalkonium chloride) may cause ocular irritation, particularly inpatients suffering from dry eye conditions or pre-existing ocularirritation. However, the single-dose packaging arrangements currentlyavailable, such as small volume plastic vials prepared by means of aprocess known as “form, fill and seal”, have several disadvantages formanufacturers and consumers. The principal disadvantages of thesingle-dose packaging systems are the much larger quantities ofpackaging materials required, which is both wasteful and costly, and theinconvenience for the consumer. Also, there is a risk that consumerswill not discard the single-dose containers following application of oneor two drops to the eyes, as they are instructed to do, but instead willsave the opened container and any composition remaining therein forlater use. This improper use of single-dose products creates a risk ofmicrobial contamination of the single-dose product and an associatedrisk of ocular infection if a contaminated composition is applied to theeyes.

While the formulations of this invention are preferably formulated as“ready for use” aqueous solutions, alternative formulations arecontemplated within the scope of this invention. Thus, for example, theactive ingredients, surfactants, salts, chelating agents, or othercomponents of the ophthalmic solution, or mixtures thereof, can belyophilized or otherwise provided as a dried powder or tablet ready fordissolution (e.g., in deionized, or distilled) water.

In still another embodiment, this invention provides kits for thepackaging and/or storage and/or use of the formulations describedherein, as well as kits for the practice of the methods describedherein. Thus, for example, kits may comprise one or more containerscontaining one or more ophthalmic preparations, tablets, or capsules ofthis invention. The kits can be designed to facilitate one or moreaspects of shipping, use, and storage.

The kits may optionally include instructional materials containingdirections (i.e., protocols) disclosing means of use of the formulationsprovided therein. While the instructional materials typically comprisewritten or printed materials, they are not limited to such. Any mediumcapable of storing such instructions and communicating them to an enduser is contemplated by this invention. Such media include, but are notlimited to electronic storage media (e.g., magnetic discs, tapes,cartridges, chips), optical media (e.g., CD ROM), and the like. Suchmedia may include addresses to internet sites that provide suchinstructional materials.

EXAMPLES

The invention, having been generally described, may be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention inany way.

Example 1 Non-Blinded, Uncontrolled Study with 0.1% Oxymetazoline inSubjects with Unilateral Ptosis

In this example, a single drop of 0.1% oxymetazoline solution was placedin the affected eye of each of five adult human subjects with unilateralptosis. Palpebral fissure was measured at baseline (pre-treatment), thenat 30 minutes and at 4 hours following treatment. Measurements weretaken with a fine point metric ruler, measuring (in mm) the centraldiameter of the palpebral fissure (i.e., sagitally across the center ofthe pupil). Results are shown in Table 1. “OD” refers to right eye; “OS”refers to left eye. “Rx” refers to which eye was treated. “% A (4 hr)”is the percent change 4 hours following treatment. All measurements arereported in mm. As shown in Table 1, 0.1% oxymetazoline verticallywidened the palpebral fissure in 5/5 (100%) of subjects, and this effectlasted at least 4 hours. The mean increase from baseline, 4 hoursfollowing treatment, was 2 mm or 31.4%.

TABLE 1 Subjects with Unilateral Ptosis Base- line 30 min 4 hr % Δ (4hr) Patient Age Rx OD OS OD OS OD OS OD OS 1 70 OS 8 6 7 9 8 9 50 2 37OS 9 8 9 9 9 9 11 3 45 OD 5 6 7 6 8 6 60 4 31 OD 9 10  10  8 10  9 11 539 OD 8 9 9 7 10  8 25

Example 2 Double-Blind, Randomized, Controlled Study with 0.1%Oxymetazoline v. Vehicle Alone in Normal Subjects

In this example, a single drop of 0.1% oxymetazoline solution wasrandomly assigned to be placed in one eye of each of five normal adulthuman subjects; a single drop of vehicle alone (negative control) wasplaced in the other eye of each subject. Palpebral fissure was measuredat baseline (pre-treatment), then at 1 hour and at 4 hours followingtreatment. Measurements were taken with a fine point metric ruler,measuring (in mm) the central diameter of the palpebral fissure (i.e.,sagitally across the center of the pupil). Results are shown in Table 2.“OD” refers to right eye; “OS” refers to left eye. “Rx” refers totreatment. “Oxy” refers to oxymetazoline; “V” refers to vehicle. “% A (4hr)” is the percent change 4 hours following treatment. All measurementsare reported in mm. As shown in Table 2, 0.1% oxymetazoline verticallywidened the palpebral fissure in 5/5 (100%) of subjects, and this effectlasted at least 4 hours. The mean increase from baseline, 4 hoursfollowing treatment, was 1.4 mm or 15.4%.

TABLE 2 Normal Subjects Base- Rx line 1 hr 4 hr % Δ (4 hr) Patient AgeOD OS OD OS OD OS OD OS OD OS 7 60 V Oxy 9 9 9 10  8 10 11 8 29 V Oxy 99 8 10  8 10 11 9 35 V Oxy 10  10  10  12 10 12 20 6 39 Oxy V 8 9 9  710  8 25 10  29 Oxy V 10  10  10   9 11 10 10

Example 3 Double-Blind, Randomized, Controlled Study with 0.1%Oxymetazoline v. Visine® L.R. in Normal Subjects

In this example, a single drop of 0.1% oxymetazoline solution wasrandomly assigned to be placed in one eye of each of ten normal adulthuman subjects; a single drop of 0.025% oxymetazoline (Visine® L.R.®,positive control) was placed in the other eye of each subject. Palpebralfissure was measured at baseline (pre-treatment), then at 30 minutes andat 3 hours following treatment. Measurements were taken with a finepoint metric ruler, measuring (in mm) the central diameter of thepalpebral fissure (i.e., sagitally across the center of the pupil).Results are shown in Table 3. “OD” refers to right eye; “OS” refers toleft eye. “Rx” refers to treatment. “Oxy” refers to 0.1% oxymetazoline;“Vis” refers to Visine® L.R.® (0.025% oxymetazoline). “% A (3 hr)” isthe percent change 3 hours following treatment. All measurements arereported in mm. As shown in Table 3, 0.1% oxymetazoline verticallywidened the palpebral fissure to a greater extent than did 0.025%oxymetazoline (Visine® L.R.®) in 9/10 (90%) of subjects. The mean changefrom baseline, 3 hours following treatment with 0.1% oxymetazoline, was1 mm or 11.2%. The mean change from baseline, 3 hours followingtreatment with 0.025% oxymetazoline, was −0.1 mm or −0.8%.

The negative mean change for subjects receiving 0.025% oxymetazolinereflects Hering's Law of equal innervation, whereby the upper eyelidwith a weaker stimulus (e.g., 0.025% oxymetazoline) will tend to drop,while the eyelid with the stronger stimulus (e.g., 0.1% oxymetazoline)will elevate.

TABLE 3 Normal Subjects Base- 30 Rx line min 3 hr % Δ (3 hr) Patient AgeOD OS OD OS OD OS OD OS Oxy Vis 12 23 Vis Oxy 10  10  10  11 10 11 10 014 35 Vis Oxy 9 10  12  11 10 10  0 11 15 60 Vis Oxy 9 9 8 11  9 10 11 018 29 Vis Oxy 9 9 9 10  9 10 11 0 20 39 Vis Oxy 9 9 9 10  9 10 11 0 1126 Oxy Vis 9 10  9 10 10  9 11 −10 13 29 Oxy Vis 9 9 11  10 11 10 22 1116 28 Oxy Vis 7 9 9  8  8  8 14 −11 17 58 Oxy Vis 9 9 11  10 11 10 22 1119 24 Oxy Vis 10  10  10   8 10  8  0 −20

Example 4 Single Drop Administration of 0.1% Oxymetazoline v. RepeatedAdministration of 0.025% Oxymetazoline (Visine® L.R.®)

A subject with pronounced ptosis of both eyelids was treated with asingle drop of Visine® L.R.® to each eye, followed 15 minutes later byadministration of a second single drop of Visine® L.R.® to each eye.Photographs of the subject's face were taken before the first and secondtreatments and again 30 minutes after the first dose. There was littleor no response to the first or second treatments. Some days later, thesame subject was treated with a single drop of oxymetazoline 0.1% toeach eye. Photographs of the subject's face were taken before treatmentand then minutes following treatment. Results are shown in FIG. 1. Thetop panel shows the subject prior to receiving the single drop of 0.1%oxymetazoline to each eye. The middle panel shows the subject 30 minutesafter receiving the single drop of 0.1% oxymetazoline to each eye. Thebottom panel shows the subject 90 minutes after receiving the singledrop of 0.1% oxymetazoline to each eye. This example shows thattreatment with a single drop of 0.1% oxymetazoline is dramatically moreeffective than repeated administration of 0.025% oxymetazoline.

Example 5 Single Drop Administration of 0.1% Oxymetazoline

A subject with moderate ptosis of the left eyelid was treated with asingle drop of 0.1% oxymetazoline administered topically to the lefteye. Photographs of her face were taken before and then 25 minutes and3.5 hours after treatment. Results are shown in FIG. 2. As shown in thefigure, the ptosis was dramatically improved, in fact essentiallyresolved during the period of observation, following treatment with thesingle drop of 0.1% oxymetazoline. Although not shown in FIG. 2, theeffect lasted at least six hours.

Example 6 Combination of Oxymetazoline and Phenylephrine

A normal adult human subject was treated with a single drop of acombination formulation of 0.1% oxymetazoline and 1.25% phenylephrine toboth eyes. Photographs of the subject's face were taken before treatmentand then 30 minutes and 45 minutes following treatment. Both eyes werewider, and both pupils were mildly dilated, at 30 and 45 minutes aftertreatment.

A second normal adult human subject was treated with a single drop of0.1% oxymetazoline to the right eye, and a single drop of a combinationformulation of 0.1% oxymetazoline and 1.25% phenylephrine to the lefteye. Photographs of the subject's face were taken before treatment andthen 30 minutes and 45 minutes following treatment. Both eyes werewider, with the left eye visibly wider than the right eye, 30 and 45minutes after treatment. The pupil of the left eye was mildly dilatedfollowing treatment as compared to before treatment and as compared tothe pupil of the right following treatment.

Example 7 Absence of Effect on Pupil Size with 0.1% Oxymetazoline inNormal Subjects

In this example, a single drop of 0.1% oxymetazoline solution was placedin each eye of six normal subjects. Pupils were measured at baseline and30 minutes following administration of oxymetazoline. Results are shownin Table 4. “OD” refers to right eye; “OS” refers to left eye.“Baseline” refers to before treatment. “30 min” refers to 30 minutesfollowing administration of 0.1% oxymetazoline). All measurements arereported in mm.

TABLE 4 Effect of Oxymetazoline 0.1% on Pupil Size (mm) in NormalSubjects Base- 30 line min Δ Patient Age Eye Color OD OS OD OS OD OS 2160 Blue 3 3 3 3 0 0 22 35 Dk Brown 4 4 4 4 0 0 23 24 Dk Brown 5 5 5 5 00 24 39 Lt Brown 5 5 5 5 0 0 25 31 Lt Brown 6 6 6 6 0 0 26 84 Blue 4 4 44 0 0

As is evident from the results shown in Table 4, 0.1% oxymetazoline hadno effect on pupil size in any of the normal subjects studied in thisexample. This lack of effect on pupil size is in stark contrast to thepupillary dilation (mydriasis) commonly obtained with other alphaagonists topically administered to the eye.

Example 8 Synergistic Lid Elevation Effect with 0.1% Oxymetazoline/0.25%Phenylephrine Combination

In this example a study was performed to assess whether the combinationof oxymetazoline 0.1% and phenylephrine 0.25% would be more potent atwidening the palpebral fissure than either of the components on theirown. A total of 7 patients were studied, 3 with ptosis and 4 withoutptosis. On a first day, each patient received a single combination dropin one eye and oxymetazoline 0.1% alone in the other. On a second day,each subject received the same single combination drop in one eye andphenylephrine 0.25% in the other eye. This method allowed a “head tohead” comparison between the two eyes. On each occasion, separation ofthe lids (mm) and pupil diameters (mm) were measured prior to treatmentand then 30 minutes after treatment (optimal time for phenylephrineeffect). Measurements were made as in the previous examples. Results areshown in Table 5 and Table 6.

TABLE 5 Combination of Oxymetazoline 0.1% and Phenylephrine 0.25% vs.Oxymetazoline 0.1% Alone Combination vs. Oxymetazoline 0.1% Alone LidsLids Rx baseline 30 mm Pupils baseline Pupils 30 min Patient ptosis ODOS OD OS OD OS OD OS OD OS 27 Yes oxy combo 10 9 11 11 4 4 4 5 28 Yescombo oxy 8 9 10 10 4 4 4 4 29 Yes combo oxy 8 9 9 8 4 4 4 4 30 No combooxy 10 10 12 11 5 5 5 5 31 No combo oxy 10 10 12 11 4 4 5 4 32 No combooxy 9 9 11 10 3 3 3 3 33 No combo oxy 10 10 12 11 5 5 6 5

TABLE 6 Combination of Oxymetazoline 0.1% and Phenylephrine 0.25% vs.Phenylephrine 0.25% Alone Combination vs. Phenylephrine 0.25% Alone LidsLids Rx baseline 30 mm Pupils baseline Pupils 30 min Patient ptosis ODOS OD OS OD OS OD OS OD OS 27 Yes phe combo 9 8 10 10 5 5 6 6 28 Yescombo phe 8 9 10 9 4 4 4 4 29 Yes combo phe 7 8 9 8 5 5 5 5 30 No combophe 10 10 12 10 5 5 6 6 31 No combo phe 10 10 12 10 3 3 4 4 32 No combophe 10 10 11 10 3 3 4 4 33 No combo phe 10 10 12 10 5 5 5 5

Results shown in Tables 5 and 6 can be summarized as follows. For allpatients, the combination of oxymetazoline 0.1% and phenylephrine 0.25%(“combo”) caused a 20% increase in lid aperture; in contrast,oxymetazoline 0.1% alone (“oxy”) caused a 7% increase in lid apertureand phenylephrine 0.25% alone (“phe”) caused only a 2% increase in lidaperture. For patients with ptosis, the combination of oxymetazoline0.1% and phenylephrine 0.25% caused a 21% increase in lid aperture,whereas oxymetazoline 0.1% alone caused a 3% increase in lid apertureand phenylephrine 0.25% alone caused a 4% increase in lid aperture. Forpatients without ptosis, the combination of oxymetazoline 0.1% andphenylephrine 0.25% caused a 19% increase in lid aperture, whereasoxymetazoline 0.1% alone caused a 10% increase in lid aperture andphenylephrine 0.25% alone (“phe”) caused no change (0% increase) in lidaperture.

It should be pointed out that the lid aperture widening withoxymetazoline alone in Table 5 is less compared to the other examplesbecause of Hering's law. (A more potent combination in the opposite eyewill diminish the effect in the eye treated with oxymetazoline alone.)

In addition, for all patients, mean pupil change with the combination ofoxymetazoline 0.1% and phenylephrine 0.25% was 0.4 mm; in contrast, meanpupil change for oxymetazoline 0.1% alone was 0 mm and for phenylephrine0.25% alone was 0.4 mm.

As can be seen from Tables 5 and 6, the combination drop exerted a moreprofound effect on lid separation than either of the two componentsalone. In fact, the combination drop exerted a more profound effect onlid separation than the sum of the effects of the two components alone,i.e., the combination of oxymetazoline 0.1% and phenylephrine 0.25%exerted a synergistic effect.

Consistent with Example 7, treatment with oxymetazoline alone caused nopupillary dilation (mydriasis). In contrast to treatment withoxymetazoline alone, there was some pupil dilation with theoxymetazoline/phenylephrine combination. However, the studiedcombination, with 0.25% phenylephrine, did not cause a clinicallysignificant mydriasis.

Example 9 Improvement in Visual Fields with 0.1% Oxymetazoline inSubjects with Ptosis

Visual field refers to the area projected onto the retina of andperceived by an eye. In a visual field test a patient places his or herface in a little “dome” and stares at a central light. Smaller targetlights illuminate in the peripheral parts of the dome, and the patientclicks a button every time he or she sees a target light. A computerrecords the number (and location) of spots seen versus not seen. Inaddition to providing a map of each eye's visual field, the test can besummarized in terms of the percent of target lights seen by each eye.For example, in a visual field test with 36 target lights, a score of25% for the left eye would indicate that only one quarter (9) of thetarget lights were seen with the left eye.

Ten patients were tested on two occasions at least one day apart, oncewith 0.1% oxymetazoline, and another time with Visine® L.R.®. A total of14 eyes were tested. In nine of the patients, 0.1% oxymetazoline wasplaced in one eye (or both eyes) on a given day, and Visine® L.R.® wasplaced in the same eye(s) on a separate day. One patient had Visine®L.R.® in one eye and 0.1% oxymetazoline in the other eye on a first day,then Visine® L.R.® and 0.1% oxymetazoline in the opposite eyes on asecond day.

Fields were measured before and after administration of drops. Resultsare shown in Table 7, and representative maps are shown in FIG. 3A-C.Visual field tests were performed serially at different times followingadministration. The results in Table 7 represent the “best” results.

TABLE 7 Effects of 0.1% Oxymetazoline and Visine ® L.R. ® on VisualField Baseline (%) After Rx (%) Δ (%) Patient Rx OD OS OD OS OD OS 0.1%Oxymetazoline 34 OS 50 42 50 56 0 14 35 OD 50 94 100 100 50 6 36 OU 5339 92 81 39 42 37 OS 83 61 100 97 17 36 38 OU 22 25 67 72 45 47 39 OS 8161 100 100 19 39 40 OS 69 19 72 47 3 28 41 OS 94 53 100 69 6 16 42 OU 5033 81 81 31 48 43 OS 78 75 97 100 19 25 43 OD 69 81 94 69 25 −12Visine ® L.R. ® 34 OS 53 47 50 53 −3 6 35 OD 61 97 100 100 39 3 36 OU 5050 78 61 28 11 37 OS 61 56 86 78 25 22 38 OU 17 25 19 31 2 6 39 OS 92 83100 92 8 9 40 OS 53 36 67 56 14 20 41 OS 94 56 94 64 0 8 42 OU 47 42 5036 3 −6 43 OS 69 81 94 69 25 −12 43 OD 78 75 97 100 19 25

Briefly, “negative control eyes” (i.e., those that didn't get any drop)showed 8% improvement. Eyes treated with Visine® L.R.® showed 11%improvement, and eyes treated with 0.1% oxymetazoline showed 35%improvement. The effect of 0.1% oxymetazoline remains striking even ifadjusted by subtracting the negative control result.

Example 10 Improvement in Visual Fields with 0.1% Oxymetazoline in aSubject with Ptosis and Glaucoma

A 78-year-old woman with bilateral ptosis and dense inferior visualfield defects in both eyes due to glaucoma was administered a singledrop of 0.1% oxymetazoline to each eye. She had essentially lost thebottom half of her vision from glaucoma (not reversible), and the tophalf of her vision from ptosis. Treatment with 0.1% oxymetazolinetemporarily restored the top parts of her visual fields by relieving herbilateral ptosis.

EQUIVALENTS

The invention has been described broadly and generically herein. Thoseof ordinary skill in the art will readily envision a variety of othermeans and/or structures for performing the functions and/or obtainingthe results and/or one or more of the advantages described herein, andeach of such variations and/or modifications is deemed to be within thescope of the present invention. More generally, those skilled in the artwill readily appreciate that all parameters, dimensions, materials, andconfigurations described herein are meant to be exemplary and that theactual parameters, dimensions, materials, and/or configurations willdepend upon the specific application or applications for which theteachings of the present invention is/are used. Those skilled in the artwill recognize, or be able to ascertain using no more than routineexperimentation, many equivalents to the specific embodiments of theinvention described herein. It is, therefore, to be understood that theforegoing embodiments are presented by way of example only and that,within the scope of the appended claims and equivalents thereto, theinvention may be practiced otherwise than as specifically described andclaimed. The present invention is directed to each individual feature,system, article, material, kit, and/or method described herein. Inaddition, any combination of two or more such features, systems,articles, materials, kits, and/or methods, if such features, systems,articles, materials, kits, and/or methods are not mutually inconsistent,is included within the scope of the present invention. Further, each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

INCORPORATION BY REFERENCE

The contents of the articles, patents, and patent applications, and allother documents and electronically available information mentioned orcited herein, are hereby incorporated by reference in their entirety tothe same extent as if each individual publication was specifically andindividually indicated to be incorporated by reference. Applicantsreserve the right physically to incorporate into this application anyand all materials and information from any such articles, patents,patent applications, or other physical and electronic document.

1-40. (canceled)
 41. A method of treating ptosis in a human patient,comprising administering oxymetazoline to the exterior surface of an eyeof the patient, wherein the oxymetazoline is formulated as apharmaceutical composition comprising about 0.05 to 0.1 weight percentoxymetazoline or a pharmaceutically acceptable salt thereof, wherein thecomposition does not include a preservative, wherein the patient doesnot have an allergic ocular condition calling for the treatment of theeye with oxymetazoline, does not have eyelid swelling, and has notundergone refractive eye surgery.
 42. The method of claim 41, whereinthe pharmaceutical composition comprises about 0.1 weight percentoxymetazoline or a pharmaceutically acceptable salt thereof.
 43. Themethod of claim 41, wherein the oxymetazoline or a pharmaceuticallyacceptable salt thereof is a pharmaceutically acceptable salt ofoxymetazoline.
 44. The method of claim 43, wherein the pharmaceuticallyacceptable salt of oxymetazoline is oxymetazoline hydrochloride.
 45. Themethod of claim 44, wherein the pharmaceutical composition comprisesabout 0.1 weight percent oxymetazoline hydrochloride based on theoxymetazoline component alone.
 46. The method of claim 41, whereinadministering the oxymetazoline comprises administering thepharmaceutical composition from a squeeze bottle or dropper capable ofdelivering a single drop with a volume of about 0.1 to 0.35 mL.
 47. Themethod of claim 46, wherein the pharmaceutical composition comprisesabout 0.1 weight percent oxymetazoline or a pharmaceutically acceptablesalt thereof.
 48. The method of claim 46, wherein administering theoxymetazoline further comprises providing a kit comprising the squeezebottle or dropper and instructional materials directing administrationof the pharmaceutical composition in a method for treating ptosis in ahuman patient.
 49. The method of claim 48, wherein the pharmaceuticalcomposition comprises about 0.1 weight percent oxymetazoline or apharmaceutically acceptable salt thereof.
 50. The method of claim 46,wherein the instructional materials direct administration of thepharmaceutical formulation as a single drop.
 51. The method of claim 41,wherein the pharmaceutical composition further comprises a lubricant.52. The method of claim 51, wherein the lubricant is selected fromartificial tears, white petrolatum, and mineral oil.
 53. The method ofclaim 41, wherein the pharmaceutical composition further comprises atear substitute.
 54. The method of claim 53, wherein the tear substituteis selected from polyols, cellulose derivatives, dextrans, water solubleproteins, carbomers, and gums.
 55. The method of claim 54, wherein thetear substitute is a cellulose derivative.
 56. The method of claim 55,wherein the tear substitute is hypromellose.
 57. The method of claim 46,wherein the squeeze bottle or dropper is a single-dose product.